Voltage-gated sodium channels (VGSC) are essential for the generation and propagation of action potentials in electrically excitable tissues (e.g. the brain, muscle, and the heart). Mutations in the VGSC SCN1A (protein name Nav1.1), underline two forms of epilepsy, Generalized Epilepsy with Febrile Seizures Plus (GEFS+) and Severe Myoclonic Epilepsy of Infancy (SMEI). To better understand the disease causing mechanism of these epilepsies, several mouse models have been generated. Electrophysiological analysis of these models suggests that a reduction in excitation of inhibitory cortical and hippocampal interneurons may underline the disease causing mutation. These electrophysiological findings have provided the first evidence for a convergent mechanism between SMEI and GEFS+ and suggest that these disorders should be considered interneuronopathies, wherein which, mutations in Scnla severely effect inhibitory interneurons and lead to epilepsy. Therefore, the overall goal of this proposal is to determine the role of Scnla on interneurons in seizure generation and propagation. To achieve this goal, our lab has generated a conditional Scnla knockout (CKO) in which exon 1 of Scnla is flanked by two loxP sites. Upon crossing the CKO with transgenic mice that express the enzyme Ore recombinase, deletion of Scnla will occur in a restricted manner based on Ore expression. The progeny from these crosses will then be evaluated for alterations in seizure threshold and spontaneous seizures. Based on our hypothesis we predict that restricted deletion of Scnla in interneurons will result in reduced seizure thresholds and spontaneous seizures, suggesting that mutations in Scnla reduce interneuron excitability, leading to seizure generation. Considering that epilepsy is the second most common neurological disorder in the U.S., more research is needed in order to better understand the mechanism of seizure generation. The results from this proposal will shed new light on the role of interneurons in seizure generation and will facilitate the development of improved therapies.